This invention relates to novel oral pharmaceutical formulations of a dose of therapeutic agent for once daily administration prior to sleep having excellent time specific controlled release properties. A substantial percentage of the controlled release dose reaches the blood stream during the dosing period of 5 to 24 hours following oral administration. The method for preparing the formulations provides pharmaceutical preparations for oral administration in both tablet and capsule dosage form.
A need exists for a dosage form that makes a drug or therapeutic agent available at a predetermined later time after administration to satisfy a therapeutic demand. The demand can arise during a circadian or chronological cycle of a patient, or there may be a demand for producing a therapeutic effect at a specific later time, such as during the morning hours to treat early morning pathologies. For example, many patients with heart disease exhibit a clinical incidence of infarction that shows a circadian distribution with high frequency in the morning hours between 4:00 a.m. and 9:00 a.m., as reported in The American Journal of Cardiology, Vol. 62, pages 635 to 637, 1988; Circulation, Vol. 82, pages 897 to 902, 1990; and Heart Disease, Vol. 2, pages 1234 to 1235, 1988. Similarly, patients suffering from arrhythmia or angina, as well as other pathologies, such as incontinence, asthma, arthritis or Parkinson""s disease exhibit an incidence of clinical symptoms in the early morning hours or upon awakening.
As is well known, the maximum time effectiveness in many pharmaceutical preparations containing a drug is only a few hours because of biological modification and elimination of the medication in the body. Consequently, repeated doses must be taken at frequent intervals to obtain long term therapeutic levels of drugs. After high initial peak concentrations, the level of drug in the blood stream continually decreases due to biological elimination, so there is little or no therapeutic effect at the end of the period between doses. As a result, the therapeutic effect fluctuates between doses corresponding to the peaks and valleys in the level of drug in blood.
Many attempts have been made to develop time-release pharmaceutical preparations which provide a more constant level of the drug in blood over several hours. Successful development of such time-release medications is greatly dependent on the pharmacokinetics of the drug used in such medications. Typically, drugs that are subject to a first pass effect are considered to have non-linear pharmacokinetics and have not been very responsive to time-release manipulations. An increase or decrease in the administered dose of these drugs will not necessarily produce the corresponding increase or decrease in observed blood levels. Thus, it is recognized that it can be difficult to design extended release formulations for compounds subjected to a first pass effect. See for example, Urquhart et al., CONTROLLED-RELEASE PHARMACEUTICALS, American Pharmaceutical Association (1979). Diltiazem is one such drug.
Diltiazem, (+)cis 3-(acetyloxy)-5-[2-(dimethylamino(ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)one, is a calcium antagonist that is utilized in the treatment of cardiovascular disorders such as angina, arrhythmias, and hypertension. Typical doses range from 120-360 mg/day. Diltiazem is sold commercially in extended release pharmaceutical diltiazem forms in order to maintain a therapeutic serum level of diltiazem and to minimize the effects of missed doses of drugs caused by a lack of patient compliance. The minimum therapeutic plasma diltiazem concentrations are in the range of about 50 to 200 ng/ml.
The activity of diltiazem in humans is directly related to its blood or plasma concentration. For illnesses which require continuous and constant control, such as hypertension and angina pectoris, diltiazem must be administered every 6 to 8 hours, as it has a very short half-life in blood of only about 3 to 4 hours. After each administration of diltiazem a succession of rapidly increasing and decreasing plasmatic diltiazem concentrations is established. Thus, the patient being treated and the target organ, more particularly the heart, are alternatively subjected to overdoses and underdoses of medicine.
The pharmacokinetics of diltiazem have been studied extensively. Diltiazem is well absorbed from the gastrointestinal tract and is subjected to an extensive first pass effect giving an absolute bioavailability of 40% (when compared with intravenous administration.) At therapeutic doses, approximately 60% of the administered diltiazem is metabolized before the compound has had a chance to reach its site of action, resulting in sub-therapeutic levels of the drug over a significant portion of the dosing period. Accordingly, it is important that the level of diltiazem maintained in blood plasma of a patient be relatively constant within the effective diltiazem range for the entire diltiazem.
In order to alleviate these drawbacks, a first form of sustained-released diltiazem known under the trade name, CARDIZEM SR.RTM., was developed and presented in the form of xe2x80x9cerodible pelletsxe2x80x9d, for once a day administration (Geoghegan et al.: U.S. Pat. Nos. 4,721,619; 4,894,240; and 5,336,504). These patents disclose a diltiazem formulation suitable for once a day administration. The formulation is prepared from diltiazem beads in which a diltiazem core is enveloped by a multilayer film having as a major component a water insoluble polymer and a minor component of a water soluble polymer. The number of layers used in the building up process, as described in the above-noted patents, is between 50 and 200 layers for the core and between 20 and 40 layers of polymer coating for the membrane.
The number of layers in the membrane and the ratio of water soluble to water insoluble polymer affects the rate of release of diltiazem from pellets. Geoghegan et al. specify that from 60% to 95% of the diltiazem should be released from the controlled release diltiazem form within 13 hours of administration. This release pattern produces peak plasma levels approximately 12-14 hours after administration.
The problem with this formulation is that optimum blood levels of diltiazem over the entire 24 hour dosing period are not maintained. Blood levels of diltiazem fall significantly before the next dose is administered resulting in a significant variance between peak and valley levels. Accordingly, although this formulation affords a reduction in peak concentration and in the number of daily intakes from 4 to 2, it does not eliminate high diltiazem blood concentration between successive medication intakes. Hence, the patient is still obliged to take the medication twice daily. Moreover, the solvent of the polymer solution used to make the membrane is constituted by organic solvents, such as isopropanol, methanol, acetone, and methylene chloride which are dangerous to use due to their flammability and toxicity, thus undesirable for an oral formulation.
U.S. Pat. No. 4,721,619 to Panoz et al. discloses a controlled absorption diltiazem formulation having a pellet of diltiazem in association with an organic acid and a lubricant, coated with a pH independent polymer. The release of 100% of diltiazem is achieved after 12 hours in vitro.
An extended-release form of diltiazem is disclosed in U.S. Pat. No. 5,288,505 to Deboeck et al. This formulation contains diltiazem as an active ingredient and a wetting agent, being coated with a microporous membrane, which membrane includes at least a water-soluble or water-dispersible polymer or copolymer and a pharmaceutically acceptable adjuvant. This formulation provides a single layer of a drug coated with several layers of membranes.
A sustained release formulation for oral administration is disclosed in U.S. Pat. No. 5,229,135 to Philippon et al. This formulation provides a pellet having a central sugar sphere and a plurality of alternating first and second layers surrounding the sphere to form a core, the first layer is a water soluble polymeric material, the second layer is diltiazem, and the outer layer is a water insoluble polymeric material. This formulation provides a single drug layer being sandwiched between water soluble and water insoluble polymers.
U.S. Pat. No. 5,286,497 to Hendrickson discloses a diltiazem formulation for Cardizem.RTM.CD, which has a xe2x80x9cstair-step release profilexe2x80x9d containing rapid release beads and extended release beads. This formulation is marketed as a once a day extended release capsule containing diltiazem and fumaric acid and provides for a blend of diltiazem beads having two dissolution profiles; rapid release profile and delayed release profile. Each of the rapid release and delayed release diltiazem beads is comprised of two parts. The first part is a central core which contains the diltiazem in association with conventional excipients (diltiazem blend), and the second part is a polymeric coating, which is a different polymer in rapid release beads, as opposed to delayed release beads.
U.S. Pat. No.5,834,023 to Chen describes a once a day controlled release diltiazem formulation which includes enteric polymeric membrane coated pellets comprising a biologically inert core which is coated with a first layer that consists of diltiazem and a polymeric binder; and a second layer that consists of a pH dependent polymeric material. The formulation additionally has a delayed pulse polymeric membrane coated pellet which contains a biologically inert core coated with diltiazem and a polymeric binder and a second polymeric membrane which is pH independent. This formulation provides a multiple cores of the biologically inert pellet in one tablet.
U.S. Pat. No. 5,788,987 to Busetti et al. discloses a therapeutic dose formulation that provides an initial delay in release of the therapeutic agent therefrom, followed by controlled release of the therapeutic agent. Release of the therapeutic agent is controlled by use of a core including the therapeutic agent, which is coated with a swellable polymeric coating. The release rate is controlled by adjusting the thickness of the coating.
It is immediately apparent in the light of the above that a pressing need exists for a dosage form that can delay the delivery of a drug, such as diltiazem to provide a drug-free interval and then deliver an effective dose of therapeutic agent specifically at a time when needed most and for a sustained period. The present invention provides such formulations.
In a first aspect of the invention there is provided a formulation for administration of a therapeutic agent for treatment of pathologies typically occurring in the morning hours, or upon awakening. The formulation of the present invention is administered once daily prior to sleep and comprises a biologically inert pellet comprising:
a drug layer comprising a dosage form of a pharmaceutical agent and a binder agent, said binder agent and said pharmaceutical agent being present in a ratio of about 0.5:20; and
a rate controlling layer comprising a water insoluble polymer, said water insoluble polymer being present in a total amount in the range of from about 5-12% of the total weight of the dosage formulation,
wherein release of the drug from the dosage formulation comprises a substantially delayed release followed by sustained release of the drug. In a preferred embodiment, the drug layer is coated with a sealing layer.
In another aspect of the invention there is provided a method of treating, preventing, or controlling hypertension or angina, in a subject in need thereof, which comprises administering to a patient in need of such treatment the dosage formulation of the invention as defined above once daily prior to sleeping.